A Double-Negative Feedback Loop between ZEB1-SIP1 and the microRNA-200 Family Regulates Epithelial-Mesenchymal Transition
Copyright policy )A Double-Negative Feedback Loop between ZEB1-SIP1 and the microRNA-200 Family Regulates Epithelial-Mesenchymal Transition
Abstract Epithelial to mesenchymal transition occurs during embryologic development to allow tissue remodeling and is proposed to be a key step in the metastasis of epithelial-derived tumors. The miR-200 family of microRNAs plays a major role in specifying the epithelial phenotype by preventing expression of the transcription repressors, ZEB1/δEF1 and SIP1/ZEB2. We show here that miR-200a, miR-200b, and the related miR-429 are all encoded on a 7.5-kb polycistronic primary miRNA (pri-miR) transcript. We show that the promoter for the pri-miR is located within a 300-bp segment located 4 kb upstream of miR-200b. This promoter region is sufficient to confer expression in epithelial cells and is repressed in mesenchymal cells by ZEB1 and SIP1 through their binding to a conserved pair of ZEB-type E-box elements located proximal to the transcription start site. These findings establish a double-negative feedback loop controlling ZEB1-SIP1 and miR-200 family expression that regulates cellular phenotype and has direct relevance to the role of these factors in tumor progression. [Cancer Res 2008;68(19):7846–54]
- University of Adelaide Australia
- Australian National University Australia
- South Australia Pathology Australia
- Hanson Institute Australia
- University of South Australia Australia
Keywords: microRNA, 570, transcription factor SIP1', microRNA, transcription factor ZEB1, mesenchyme cell, epithelium cell, microRNA 200b, epithelial-mesenchymal transition, microRNA 200a, feedback, Nerve Tissue Proteins, animal cell, Models, Biological, epi, E-Box Elements, Mesoderm, Mice, Dogs, cistron, binding kinetics, Animals, Humans, controlled study, RNA, Messenger, Promoter Regions, Genetic, transcription factor, Cells, Cultured, Feedback, Physiological, Homeodomain Proteins, microRNA, E box element, microRNA 429, article, RNA-Binding Proteins, Zinc Finger E-box-Binding Homeobox 1, embryo development, Epithelial Cells, ZEB, unclassified drug, MicroRNAs, Gene Expression Regulation, Multigene Family, transcription, transcription factor ZEB1, Transcription Factors
Keywords: microRNA, 570, transcription factor SIP1', microRNA, transcription factor ZEB1, mesenchyme cell, epithelium cell, microRNA 200b, epithelial-mesenchymal transition, microRNA 200a, feedback, Nerve Tissue Proteins, animal cell, Models, Biological, epi, E-Box Elements, Mesoderm, Mice, Dogs, cistron, binding kinetics, Animals, Humans, controlled study, RNA, Messenger, Promoter Regions, Genetic, transcription factor, Cells, Cultured, Feedback, Physiological, Homeodomain Proteins, microRNA, E box element, microRNA 429, article, RNA-Binding Proteins, Zinc Finger E-box-Binding Homeobox 1, embryo development, Epithelial Cells, ZEB, unclassified drug, MicroRNAs, Gene Expression Regulation, Multigene Family, transcription, transcription factor ZEB1, Transcription Factors
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